Embryogenesis of tracheo esophageal anomalies: a review

Abstract

The embryology of the normal esophagus and trachea is controversial. There are two main opinions regarding the role played by the tracheoesophageal (TE) septum. Similar controversy exists in explaining the embryology of anomalous TE development, mainly due to a lack of embryos demonstrating these anomalies at critical stages during development. Proposed theories can be divided into four main groups: intraembryonic pressure; epithelial occlusion; differential growth; and vascular occlusion. More recently, a new theory has been described based on analysis of anomalous TE development in adriamycin (doxorubicin)-exposed rat embryos. Impaired tracheal development, with the foregut developing into the trachea rather than the esophagus and associated with development of a dorsal pouch from the upper part of the foregut, gave rise to esophageal atresia with distal TE fistula. On the other hand, development of a ventral upper foregut pouch led to tracheal atresia. A laryngotracheo-esophageal cleft may result if no upper foregut pouches develop, with differentiation of the ventral half of the foregut into trachea and the dorsal half into esophagus. This review describes the basic theories of normal and abnormal TE development in mammalian embryos and presents new data related to this abnormality.

Intrinsic esophageal innervation in esophageal atresia without fistula

“…The muscle layers are of striated fibres in the upper pouch and of smooth fibres in the distal segment. There is no fistula communicating the trachea and the esophagus and it is difficult to understand the embryogenesis even under the light of the recent investigations in the adriamycin rat model [9,10]. In our extensive experience on the adriamycin rat model of EA/TEF, we never saw isolated EA and this has only been found in one instance by another group [37,38].…”

“…Distorted gastroesophageal anatomy and the neonatal operation account in part for this phenomenon but malformative elements likely contribute to it. EA with TEF results from an imbalance of the development of the dorsal and ventral components of the foregut during tracheoesophageal separation in the embryo [9,10] shortly after the foregut has been populated by migrating neuroblasts from the cranial neural crest and at the time when the vagus and laryngeal nerves are being patterned [11,12]. It is therefore not surprising for the extrinsic and intrinsic innervations to be abnormal in both human and experimental animals with EA and TEF.…”

Adriamycin-Induced Models of VACTERL Association

“…This defect is identical to Gross classification C type OA/TOF, the most common anatomical variant seen in humans (86%) [Harmon and Coran, 1998]. The upper oesophageal blind-ending pouch was seen to arise from the dorsal wall of the distal pharynx, lined with stratified squamous epithelium, and end at the level of cricoid cartilage [Merei and Hutson, 2002]. Beasley et al [2004] reported pouch development from the dorsal wall of the distal pharynx at E15 in the ARM, and this late outgrowth of a pouch was also described by Possoegel et al [1998].…”

Adriamycin mouse model: a variable but reproducible model of tracheo-oesophageal malformations

“…However, in 1982, Zaw-Tun [12] analysed early developmental stage human embryos and demonstrated that the respiratory primordium grows caudally from the ventral aspect of the foregut. Through detailed histological accounts of early gestation ARM embryos, an understanding of the dysmorphogenesis of oesophageal atresia and tracheal agenesis has been gained [13]. Morphological patterning and tissue differentiation in organogenesis is controlled by spatial and temporal coordinated signalling systems mediated by transcription factors and secreted proteins.…”